Consumer medicine information

ZEDD

Azithromycin

BRAND INFORMATION

Brand name

Zedd Tablets

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ZEDD.

What is in this leaflet

This leaflet answers some common questions about ZEDD.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ZEDD against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What ZEDD is used for

ZEDD is used to treat bacterial infection including the following:

  • respiratory infections such as sinusitis, sore throat, tonsillitis, bronchitis and pneumonia
  • skin and underlying tissue infections
  • genital infections such as Chlamydia
  • an uncommon eye infection (Chlamydia trachomatis conjunctivitis and trachoma).

ZEDD may also be used to prevent infections by bacterium called Mycobacterium avium-intracellulare Complex.

ZEDD is an antibiotic which belongs to a group of medicines called azalides, a subclass of the macolide antibiotics. It works by killing or stopping the growth of bacteria causing your infection.

ZEDD does not work against viral infections such as colds or flu.

Your doctor may have prescribed ZEDD for another reason. Ask your doctor if you have any questions about why ZEDD has been prescribed for you.

ZEDD is available only with a doctor's prescription.

Before you take ZEDD

When you must not take it

Do not take ZEDD if you are allergic to:

  • azithromycin
  • any other macrolide antibiotics such as clarithromycin, erythromycin and roxithromycin
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itchiness or hives, swelling of the face, lips or tongue (which may cause difficulty in swallowing), shortness of breath, wheezing or difficulty breathing.

Do not take ZEDD if the expiry date (Exp.) printed on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work as well.

Do not take ZEDD if the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

Your doctor will discuss the risks and benefits of taking ZEDD during pregnancy.

Tell your doctor if you are breastfeeding.

Your doctor will discuss the risks and benefits of taking ZEDD while breastfeeding.

Tell your doctor if you have liver or kidney problems or any other medical conditions.

If you have not told your doctor about any of the above, tell them before you start taking ZEDD.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by ZEDD or may affect how well it works. These include:

  • some medicines for migraine or headache such as ergotamine or dihydroergotamine
  • oral contraceptives
  • antacids, medicines used to treat indigestion
  • coumarin-type Oral Anticoagulants (a medicine used to prevent blood clots)
  • digoxin, a medicine used to treat heart failure
  • cyclosporin, a medicine used to treat certain problems with the immune system
  • terfenadine or astemizole, medicines used to treat hayfever and allergies
  • zidovudine, a medicine used to treat patients with AIDS.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have more information on medicines to be careful with or avoid while taking ZEDD.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

How to take ZEDD

How much to take

Your doctor will tell you how many tablets you need to take and when to take them. This depends on the type of your infection.

It is recommended that you take the tablet on an empty stomach.

Follow all directions given to you by your doctor and pharmacist carefully.

If you forget to take ZEDD

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take two doses at a time to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take ZEDD

Do not stop taking ZEDD until you finish the pack unless recommended by your doctor. Do not stop taking it just because you are feeling better.

If you do not take the full course prescribed by your doctor, your infection may not clear completely or your symptoms may return.

If you take too much ZEDD (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13  11  26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ZEDD. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too many tablets, you may get an upset stomach, diarrhoea or skin rashes.

While you are taking ZEDD

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ZEDD.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking ZEDD.

If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.

If you get a sore, white mouth or tongue while taking, or soon after stopping ZEDD, tell your doctor. Also tell your doctor if you get vaginal itching or discharge.

This may mean you have a yeast infection called thrush. Sometimes the use of ZEDD allows yeast to grow and the above symptoms to occur. ZEDD does not work against yeast.

Things you must not do

Do not use ZEDD to treat any other conditions unless your doctor tells you to.

Do not give ZEDD to anyone else, even if they have the same condition as you.

Things to be careful of

Protect your skin when you are in the sun, especially between 10am and 3pm.

Some azalide antibiotics may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness or a severe sunburn.

If outdoors, wear protective clothing and use a 30+ sunscreen. If your skin does appear to be burning, stop taking ZEDD and tell your doctor immediately.

Talk to your doctor about the need for additional contraception while taking ZEDD.

Some antibiotics may decrease the effectiveness of some birth control pills, although this has not been shown with ZEDD.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ZEDD.

Like all other medicines, ZEDD may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • white, furry sore tongue and mouth
  • sore, itchy vagina with a white discharge
  • nausea, vomiting
  • loss of appetite
  • stomach pain, indigestion
  • wind, constipation, loose bowel motions
  • unusual weight gain or swelling of the arms and legs
  • dizziness
  • headache
  • muscle or joint aches
  • hearing loss or ringing in the ears.

These are generally mild side effects.

If any of the following happen, stop taking ZEDD and tell your doctor immediately:

  • diarrhoea (loose bowel motions)
  • palpitations (fast or irregular heart beat)
  • chest pain
  • asthma, wheezing or shortness of breath
  • symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
  • swelling of the face, lips or tongue which may lead to difficulty swallowing or breathing
  • hives, itching or skin rash
  • fainting
  • yellowing of the eyes or skin, also called jaundice
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • blood in the urine or bowel motions
  • severe blistering or peeling of the skin
  • convulsions (fits).

These are serious but rare side effects.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

Tell your doctor immediately if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with ZEDD:

  • severe stomach cramps
  • watery and severe diarrhoea, which may be bloody
  • fever, in combination with one or both of the above.

These are rare but serious side effects. ZEDD can cause some bacteria, which are normally present in the bowel and normally harmless to multiply and therefore cause the above symptoms. You may need urgent medical attention. Do not take any medicine for this diarrhoea without first checking with your doctor.

After using ZEDD

Storage

Keep ZEDD where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store ZEDD or any other medicine in the bathroom or near a sink.

Do not leave ZEDD in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking ZEDD, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ZEDD comes as:

  • ZEDD 500 - white capsule-shaped tablet marked “AT|500” and “>” on the reverse. Each blister pack contains 3 tablets.

Ingredients

The active ingredient in ZEDD is azithromycin (as monohydrate).

  • each ZEDD 500 tablet contains 500 mg of azithromycin
  • The tablets also contain:
  • calcium phosphate
  • pregelatinised maize starch
  • croscarmellose sodium
  • sodium lauryl sulfate
  • magnesium stearate
  • Opadry AMB white OY-B-28920.

The tablets are gluten free .

Sponsor

Spirit Pharmaceuticals Pty Ltd
117 Harrington Street,
The Rocks, Sydney NSW 2000
Australia
Phone: 1800 065 772

Distributor

Sigma Pharmaceuticals (Australia) Pty Ltd
96 Merrindale Drive
Croydon Vic 3136
Australia

Australian registration number:
ZEDD 500 - AUST R 107602

Date of preparation
April 2009

® Registered Trade Mark

BRAND INFORMATION

Brand name

Zedd Tablets

Active ingredient

Azithromycin

Schedule

S4

 

Name of the medicine

Azithromycin (as monohydrate).

Excipients.

Calcium phosphate, pregelatinised maize starch, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate and Opadry AMB White OY-B-28920. The tablets are gluten free.

Description

Chemical name: 9-deoxo-9a-aza-9a-methyl- 9a-homoerythromycin A. Molecular formula: C38H72N2O12.H2O. MW: 767.01. CAS: 83905-01-5. Azithromycin monohydrate is a white or almost white powder.

Pharmacology

Microbiology.

Azithromycin demonstrates activity in vitro against a wide range of bacteria including the following.

Gram positive aerobic bacteria.

Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic Streptococci), Streptococcus pneumoniae, alpha-haemolytic Streptococci (viridans group) and other Streptococci and Corynebacterium diphtheriae. Azithromycin demonstrates cross resistance with erythromycin resistant gram positive strains, including Enterococcus faecalis (enterococcus) and most strains of methicillin resistant Staphylococci.

Gram negative aerobic bacteria.

Haemophilus influenzae (including beta-lactamase producing Haemophilus influenzae), Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholerae, Vibrio parahaemolyticus and Plesiomonas shigelloides.
Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility tests should be performed.
Proteus species, Serratia species, Morganella species and Pseudomonas aeruginosa are usually resistant.

Anaerobic bacteria.

Bacteroides fragilis and Bacteroides species, Clostridium perfringens, Peptococcus species and Peptostreptococcus species, Fusobacterium necrophorum and Propionibacterium acnes.

Organisms of sexually transmitted diseases.

Azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae and Haemophilus ducreyi.

Other organisms.

Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter species and Listeria monocytogenes.

Opportunistic pathogens associated with HIV infections.

Mycobacterium avium-intracellulare complex.
Azithromycin demonstrates activity in vivo against the following bacteria.

Gram positive aerobic bacteria.

Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic Streptococci), Streptococcus pneumoniae, alpha-haemolytic Streptococci (viridans group) and other Streptococci.

Gram negative aerobic bacteria.

Haemophilus influenzae (including beta-lactamase producing Haemophilus influenzae), Haemophilus parainfluenzae, Moraxella catarrhalis.

Other organisms.

Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae.

Opportunistic pathogens associated with HIV infections.

Mycobacterium avium-intracellulare complex MAC.
In Australia, macrolide resistance for Streptococcus pneumoniae and Staphylococcus aureus has been increasing since the late 1990s. Resistance rates of 15% or more are regularly reported. The use of macrolides should be guided by culture susceptibility results and practice guidelines.

Susceptibility tests.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of ‘susceptible’ indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of ‘intermediate’ indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of ‘resistant’ indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Susceptibility testing for Mycobacterium avium complex (MAC).

The disc diffusion techniques and dilution methods for susceptibility testing against Gram positive and Gram negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against Mycobacterium avium complex (MAC) organisms have not been established or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilisation of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible to azithromycin have not been established.

Pharmacokinetics.

Following oral administration of a 500 mg dose, azithromycin is absorbed from the gastrointestinal tract with an absolute bioavailability of 37%. Maximum serum concentration (Cmax) of 0.3 to 0.4 microgram/mL is achieved in two to three hours with an AUC(0 to 24) of 2.6 microgram.hour/mL.
Pharmacokinetics in elderly subjects are substantially the same and no dosage adjustment is necessary. The extent of absorption is unaffected by coadministration with antacid; however, Cmax is reduced by up to 30%. Administration of cimetidine 800 mg two hours prior to azithromycin had no effect on azithromycin absorption. Azithromycin did not affect the plasma levels or pharmacokinetics of carbamazepine, methylprednisolone, zidovudine or multiple oral doses of theophylline (see Interactions with Other Medicines).
Serum concentrations decline in a polyphasic pattern, resulting in an average terminal half-life of 68 hours. The high values for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/minute) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Azithromycin concentrations in the cerebrospinal fluid are very low. Concentrations in the peritoneal fluid are also very low.
Azithromycin is distributed widely throughout the body. Rapid movement of azithromycin from blood into tissues results in significantly higher azithromycin concentrations in tissue than in plasma (from 1 to 60 times the maximum observed concentration in plasma). It appears to be concentrated intracellularly. Concentrations in tissues, e.g. lung, tonsil and prostate, exceed the MIC90 for likely pathogens after a single dose of 500 mg, and remain high after serum or plasma concentrations decline to below detectable levels. Mean peak concentrations observed in peripheral leucocytes, the site of MAC infection, were 140 microgram/mL and remained above 32 microgram/mL for approximately 60 hours following a single 1,200 mg oral dose.
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 microgram/mL to 7% at 2 microgram/mL.
Approximately 12% of an intravenously administered dose is excreted in the urine over three days as the parent drug, the majority in the first 24 hours. Biliary excretion of azithromycin is a major route of elimination for unchanged drug following oral administration. Very high concentrations of unchanged drug have been found, together with ten metabolites, formed by N and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assays in tissues suggests that metabolites play no part in the microbiological activity of azithromycin.
Following a single oral dose of azithromycin 1 gram, the pharmacokinetics in subjects with mild to moderate renal impairment (GFR 10-80 mL/minute) were not affected. Statistically significant differences in AUC0-120 (8.8 microgram.hour/mL versus 11.7 microgram.hour/mL), Cmax (1.0 microgram/mL versus 1.6 microgram/mL) and Clr (2.3 mL/minute/kg versus 0.2 mL/minute/kg) were observed between subjects with severe renal impairment (GFR < 10 mL/minute) and subjects with normal renal function. In patients with mild (class A) to moderate (class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance.
Azithromycin did not affect prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients.

Clinical Trials

Disseminated MAC disease prophylaxis.

In a placebo controlled study patients receiving azithromycin were less than one-half as likely to develop MAC bacteraemia as those on placebo. The one year cumulative incidence rate of disseminated MAC disease was 8.24% on azithromycin and 20.22% on placebo.
In a comparative study the risk of developing MAC bacteraemia in patients receiving azithromycin was less than that observed for patients receiving rifabutin. Patients on a combination of azithromycin and rifabutin were approximately one-third as likely to develop MAC bacteraemia as those patients receiving either agent alone. The one year cumulative incidence rate of disseminated MAC disease was 7.62% on azithromycin, 15.25% on rifabutin and 2.75% on azithromycin and rifabutin. However, patients receiving the combination were more likely to discontinue therapy due to poor tolerability.

Trachoma in adults and children.

Information from clinical trial data and published reports of studies supports the efficacy of 20 mg/kg to 1 g, taken either as a single dose or once weekly for up to three weeks, in the treatment of trachoma in children and adults. The single dose schedule has not been compared with the three weekly dosing schedule in clinical trials.

Repeat courses for trachoma.

While the statistically significant superiority of a single dose of azithromycin given as a single dose and repeated at six months versus a single dose of azithromycin to adults or children with active trachoma has not been determined, information from clinical trial data suggests that the trachoma free period may be extended by a repeat single dose of azithromycin at six months.

Indications

Treatment of the following infections of mild to moderate severity in adults.

Lower respiratory tract infections.

Acute bacterial bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis.
Community acquired pneumonia due to Strep. pneumoniae or Haemophilus influenzae in patients suitable for outpatient oral treatment.

Upper respiratory tract infections.

Acute sinusitis due to Streptococcus pneumoniae or Haemophilus influenzae.
Acute streptococcal pharyngitis.

Note.

Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin appears to be almost as effective in the treatment of streptococcal pharyngitis. However, substantial data establishing the efficacy of azithromycin in the subsequent prevention of rheumatic fever are not available at present.

Uncomplicated skin and skin structure infections.

Uncomplicated infections due to Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiae. Abscesses usually require surgical drainage.

Sexually transmitted disease.

Uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

Note.

At the recommended dose azithromycin cannot be relied upon to treat gonorrhoea or syphilis. As with other drugs for the treatment of nongonococcal infections, it may mask or delay the symptoms of incubating gonorrhoea or syphilis. Appropriate tests should be performed for the detection of gonorrhoea or syphilis and treatment should be instituted as required.
Azithromycin is also indicated for the treatment of Chlamydia trachomatis conjunctivitis and trachoma.
Azithromycin is also indicated for the prevention of infection due to Mycobacterium avium-intracellulare complex (MAC) disease, when used as the sole agent or in combination with rifabutin at its approved dose, in adults and children aged more than 12 years with HIV infection and CD4 cell count less than or equal to 75 cells/microlitre (see Precautions). Disseminated infection due to Mycobacterium avium-intracellulare complex should be excluded by a negative blood culture prior to commencement of therapy.

Contraindications

Known hypersensitivity to azithromycin, erythromycin or any other macrolide antibiotic or to any of the inactive ingredients in the product (see Excipients).

Precautions

Use with caution in the following circumstances. In the treatment of pneumonia, azithromycin has been shown to be safe and effective only in the treatment of community acquired pneumonia of mild severity due to Streptococcus pneumoniae or Haemophilus influenzae in patients appropriate for outpatient oral therapy. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis; patients with nosocomially acquired infections; patients with known or suspected bacteraemia; patients requiring hospital admission; elderly or debilitated patients; patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including azithromycin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases may respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Hypertoxin producing strains of Clostridium difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine (e.g. Lomotil), may prolong and/or worsen the condition and should not be used.
Rare, serious, allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported in patients on azithromycin therapy (see Contraindications). Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Doctors should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Ventricular arrhythmias associated with prolonged QT interval, including ventricular tachycardia and torsades de pointes, have been reported with macrolide products. Azithromycin should be used with caution in patients predisposed to QT interval prolongation or in patients taking other medications known to prolong the QT interval.
In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be coadministered.
As with any antibiotic preparation, observation for signs of superinfection with nonsusceptible organisms, including fungi, is recommended.
The majority of cases of disseminated Mycobacterium avium complex infection occur in patients with CD4 counts below 50 cells/microlitre. Some authorities recommend delay of initiation of prophylaxis until the cell count has fallen to 50 cells/microlitre.
No evidence exists from formal studies to determine the need for, and frequency of, repeat dosing in the treatment of trachoma.

Impaired renal function.

No dose adjustment is needed in patients with mild or moderate renal impairment. After oral administration of a single dose of azithromycin 1 g in subjects with severe renal impairment (GFR < 10 mL/minute), mean AUC0-120h and mean Cmax were increased by approximately 30 and 60%, respectively, when compared to subjects with normal renal function. Thus, caution should be exercised before prescribing azithromycin to these patients.

Impaired hepatic function.

In patients with mild (class A) to moderate (class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease (see Pharmacokinetics).

Carcinogenicity/ mutagenicity.

No studies have been done to determine the carcinogenic potential of azithromycin in animals. Azithromycin showed no genotoxic potential in a range of standard laboratory tests for gene mutations and chromosomal damage. In three fertility and general reproduction studies in rats, there was decreased fertility at doses of 20 and 30 mg/kg/day. The clinical significance of this is unknown.

Use in pregnancy.

(Category B1)
No studies have been carried out in pregnant women. Azithromycin was not fetotoxic or teratogenic in mice and rats at doses that were moderately maternotoxic (up to 200 mg/kg/day). At 200 mg/kg/day, mouse and rat fetal tissues homogenate concentrations were five to tenfold higher than corresponding maternal plasma concentrations.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Use in lactation.

There are no data on the possible excretion of azithromycin in animal or human milk. Azithromycin should only be used in lactating women where adequate alternatives are not available.

Interactions

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome metabolite complex does not occur with azithromycin.

Drugs that should not be concomitantly administered with azithromycin.

Antacids.

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by up to 30%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.

Ergot.

The theoretical possibility of ergotism contraindicates the concurrent use of azithromycin with ergot derivatives (see Precautions).

Drugs that require dosage adjustment when administered concomitantly with azithromycin.

Cyclosporin.

In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for three days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Drugs that have been studied with no clinically significant interaction shown.

Atorvastatin.

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).

Carbamazepine.

In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cetirizine.

In healthy volunteers, coadministration of a five day regimen of azithromycin with cetirizine 20 mg at steady state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Cimetidine.

In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given two hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin type oral anticoagulants.

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single warfarin 15 mg dose administered to healthy volunteers. There have been reports received in the postmarketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin type oral anticoagulants.

Didanosine.

Coadministration of azithromycin 1,200 mg/day with didanosine 400 mg/day in six HIV positive subjects for two weeks had no effect on the steady-state pharmacokinetics of didanosine as compared with placebo.

Efavirenz.

Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for seven days did not result in any clinically significant pharmacokinetic interactions. No dose adjustment is necessary when azithromycin is given with efavirenz.

Fluconazole.

Coadministration of a single dose of 1,200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole however a clinically insignificant decrease in Cmax (18%) of azithromycin was observed. No dose adjustment is necessary when azithromycin is given with fluconazole.

Indinavir.

Coadministration of a single dose of 1,200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for five days. No adjustment of the dose is necessary when azithromycin is given with indinavir.

Methylprednisolone.

In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam.

In healthy volunteers, coadministration of azithromycin 500 mg/day for three days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir.

Coadministration of 1200 mg azithromycin and nelfinavir (750 mg three times daily to steady state) produced no clinically significant effect. Dose adjustment is not necessary.

Rifabutin.

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment with azithromycin and rifabutin. Although neutropenia has been associated with use of rifabutin, a causal relationship to combination with azithromycin has not been established.

Sildenafil.

In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for three days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Terfenadine, astemizole.

In a study in normal subjects addition of azithromycin did not result in any significant changes in cardiac repolarisation (QTc interval) measured during the steady-state dosing of terfenadine. However, there have been cases reported where the possibility of such an interaction could not be entirely excluded.

Theophylline.

There is no evidence of any pharmacokinetic interaction when azithromycin and theophylline are coadministered to healthy volunteers.

Triazolam.

In 14 healthy volunteers, coadministration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg triazolam on day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/ sulfamethoxazole.

Coadministration of trimethoprim/ sulfamethoxazole DS (160 mg/800 mg) for seven days with azithromycin 1,200 mg on day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies. No dose adjustment is necessary.

Zidovudine.

Single 1,000 mg doses and multiple 1,200 or 600 mg doses of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear.

Other interactions.

Digoxin.

Some of the macrolide antibiotics have been reported to impair the metabolism of digoxin (in the gut) in some patients. In patients receiving concomitant azithromycin, a related azalide antibiotic, and digoxin, the possibility of raised digoxin levels should be borne in mind.

Laboratory tests.

There are no reported laboratory test interactions.

Adverse Effects

In clinical trials, most of the reported adverse events were mild to moderate in severity and were reversible on discontinuation of the drug. Approximately 0.7% of patients discontinued azithromycin therapy because of treatment related adverse events. Most of the adverse events leading to discontinuation were related to the gastrointestinal tract, e.g. nausea, vomiting, diarrhoea or abdominal pain. Rare but potentially serious adverse events were angioedema (one case) and cholestatic jaundice (one case).
Hearing impairment has been reported in investigational studies, mainly where higher doses were used, for prolonged periods of time. In those cases where follow-up information was available the majority of these events were reversible.

Clinical trials.

Multiple dose regimen.

Overall, the most common adverse events in patients receiving the multiple dose regimen of azithromycin were related to the gastrointestinal system with diarrhoea/ loose stools (5%), nausea (3%) and abdominal pain (3%) being the most frequently reported. No other adverse events occurred in patients on the multiple dose regimen with a frequency > 1%. Adverse events that occurred with a frequency of 1% or less included the following.

Allergic.

Rash, photosensitivity and angioedema.

Cardiovascular.

Palpitations, chest pain.

Gastrointestinal.

Dyspepsia, flatulence, vomiting, melaena, cholestatic jaundice.

Genitourinary.

Moniliasis, vaginitis, nephritis.

Nervous system.

Dizziness, headache, vertigo, somnolence.

General.

Fatigue.

Single 1 g dose regimen.

Overall, the most common adverse events in patients receiving a single dose regimen of azithromycin 1 g were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple dose regimen. Adverse events that occurred in patients on the single 1 g dosing regimen of azithromycin with a frequency of 1% or greater included diarrhoea/ loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), vaginitis (2%) and dyspepsia (1%).

Laboratory abnormalities.

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows.

Incidence 1 to 2%.

Elevated serum creatine phosphokinase, potassium, alanine aminotransferase (ALT, SGPT), γ-glutamyl transferase (GGT) and aspartate aminotransferase (AST, SGOT), lymphocytes and neutrophils; decreased neutrophils.

Incidence < 1%.

Leucopenia, neutropenia, decreased platelet count; elevated serum alkaline phosphatase, bilirubin, blood urea nitrogen (BUN), creatinine, blood glucose, lactate dehydrogenase (LDH) and phosphate, monocytes, basophils, bicarbonate; decreased sodium, potassium.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple dose trials involving > 3,000 patients, three patients discontinued therapy because of treatment related liver enzyme abnormalities and one because of a renal function abnormality.

HIV infected patients receiving prophylaxis for disseminated MAC.

The most frequent (> 5% in any treatment group) treatment related adverse events in this group are shown in Table 1.
The most common laboratory test abnormalities were haematological (mainly decreases in haemoglobin and white cell count) and increases in AST and ALT.

Postmarketing experience.

In postmarketing experience, the following adverse events have been reported.

Infections and infestations.

Moniliasis and vaginitis.

Blood and lymphatic system disorders.

Thrombocytopenia.

Body as a whole.

Asthenia, anaphylaxis (rarely fatal), fatigue and malaise.

Cardiovascular.

Hypotension; palpitations and arrhythmias including ventricular tachycardia have been reported. There have been rare reports of QT prolongation and torsades de pointes.

Central and peripheral nervous system.

Dizziness, somnolence, headache, syncope, convulsions, hypotensia, paraesthesia and hyperactivity.

Gastrointestinal.

Vomiting/ diarrhoea (rarely resulting in dehydration), dyspepsia, pancreatitis, anorexia, constipation, pseudomembranous colitis, rare reports of tongue discolouration.

Genitourinary.

Acute renal failure, interstitial nephritis.

Liver/ biliary.

Abnormal liver function including hepatitis and cholestatic jaundice, hepatic necrosis and hepatic failure, which have rarely resulted in death.

Musculoskeletal.

Arthralgia.

Psychiatric.

Aggressive reaction, nervousness, agitation, anxiety.

Skin/ appendages.

Pruritus, urticarial, oedema, angioedema, serious skin reactions including erythema multiforme, rash, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Special senses.

Vertigo, hearing disturbances* including hearing loss, deafness and/or tinnitus. Taste/ smell perversion and/or loss.
*Hearing impairment has been reported with macrolide antibiotics.

Dosage and Administration

Zedd should be given as a single daily dose on an empty stomach.

Adults.

Sexually transmitted uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

1 g as a single oral dose.

Conjunctivitis and trachoma due to Chlamydia trachomatis.

1 g either as a single dose or once weekly for up to three weeks (see Clinical Trials).

All other indications (except prevention of disseminated Mycobacterium avium complex disease).

Total dose of 1.5 g, given as 500 mg on day 1, then 250 mg daily on days 2 to 5 or, alternatively, 500 mg daily for three days.

Prevention of disseminated Mycobacterium avium complex disease.

Total dose of 1,200 mg taken once weekly, either alone or in combination with rifabutin, at its recommended dosage.

Overdosage

There are no data available on overdosage. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
As with many cationic amphiphilic drugs, phospholipidosis has been observed in some tissues of mice, rats and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems in dogs administered doses which, based on pharmacokinetics, are as low as two to three times greater than the recommended human dose and in rats at doses comparable to the human dose. This effect is reversible after cessation of azithromycin treatment. The significance of these findings for humans with overdose of azithromycin is unknown.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Tablets (white to off white, marked > on one side), 500 mg (capsule shaped, marked AT/500 on reverse): 2's*, 3's (blister pack); 600 mg* (oval, marked AT/600 on reverse): 8's (blister pack).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.